Challenges and Promise of Human Immunodeficiency Virus Remission

Abstract

Antiretroviral therapy effectively controls human immunodeficiency virus (HIV) replication but it is unable to fully eradicate the HIV reservoir and treatment must be life-long. Progress toward a strategy for HIV remission will require overcoming key hurdles to fill gaps in our understanding of HIV persistence, but the identification of individuals who have attained sterilizing or functional HIV cure show that such a goal is achievable. In this review, we first outline challenges in targeting the HIV reservoir, including difficulties identifying HIV-infected cells, ongoing work elucidating the complex intracellular environment that contribute to HIV latency, and barriers to reactivating and clearing the HIV reservoir. We then review reported cases of HIV sterilizing cure and explore natural models of HIV remission and the promise that such HIV spontaneous and posttreatment controllers may hold in our search for a broadly-applicable strategy for the millions of patients living with HIV.

Keywords: HIV reservoir; latency; post-treatment controller; provirus; spontaneous controller.

Figure 1.

Challenge of identifying and reactivating human immunodeficiency virus (HIV)–infected cells. A, CD4⁺ T cells harboring HIV proviral DNA are rare among the total CD4⁺ T-cell population; most of the proviral DNA is defective, and only <10% is intact. B, HIV-infected cells are mostly located in difficult-to-study anatomic sites, including lymph nodes, intestinal lymphoid tissue, and spleen. C, Multiple potential mechanisms contribute to HIV latency, including epigenetic modifications, depletion of transcriptional factors, and integration in dense regions of the chromosome. Even the most potent CD4⁺ T-cell–activating agents (eg, phytohemagglutinin [PHA]) are only able to activate a small proportion of CD4⁺ T cells harboring intact HIV proviruses, and the underlying mechanisms remain elusive. D, HIV achieves sequence diversity very early during infection; sequences obtained from different cell and anatomic compartments demonstrate substantial diversity as shown in this example phylogenetic analysis of intact HIV proviral sequences from 1 participant. Figures were generated with BioRender.com.